Drugs for Parkinon’s disease

1. Drugs for Parkinon’s disease • Parkinson's disease • progressive tremor • Bradykinesia and rigidity • degeneration of the dopaminergicnigrostriatal pathway • decrease in the striatal concentrationof dopamine • presence of Lewybodies

2. Degeneration of the nigrostriatal pathway leads to the depletionof the neurotransmitter dopamine • therapyinvolved the administration of its precursor levodopaoragents that mimic the action of dopamine

3. Drug Therapy • Decrease cholinergic activity within Basal Ganglia • Activating Dopamine receptors in SubstantiaNigra feeding back to Cholinergic Cells in the striatum • Antagonize Acetylcholine receptors

4. Antiparkinsonian Drugs • Symptomatic Therapy • The traditional approach to treating patients with Parkinson'sdisease is the administration of drugs to alleviate symptoms. • Anticholinergic Agents and Amantadine • Levodopa • Synthetic Dopamine Agonists

5. Anticholinergic Agents • Act by correcting the balance between dopamineand acetylcholine • trihexyphenidyl and benztropine • Antagonists at muscarinic receptors • raise the concentration of dopamine in the synapticcleft

6. Anticholinergic Agents • adverse effects • impairment of memory andhallucinations • impaired ocular accommodation • dryness of the mouth • Constipation • urinary retention • vasodilatation

7. Amantadine • resembles the anticholinergic drugs • appears to enhance synthesis, release, or reuptake of dopamine from the surviving Nigral Neurons • often results in some improvement in rigidityand bradykinesia. • induce ankle edema and livedoreticularisof the legs

8. Levodopa • the cornerstone of symptomatic therapy • decarboxylatedto dopamine • usually administered with a peripheral decarboxylaseinhibitor

9. L Dopa- Pharmacokinetics • L Dopa is readily absorbed from GI Tract • Large amount of L Dopa has to be given due to First Pass Effect • L Dopa metabolized by dopadecarboxylase in liver and periphery to dopamine • Secreted in urine unchanged or conjugated with glucoronyl sulfate • Most of L Dopa converted to NE and EPI

10. Effects of L Dopa on the Symptoms of Parkinson Disease • L Dopa fairly effective in eliminating most of the symptoms of Parkinson Disease • Bradykinesia and rigidity respond quickly • Reduction in tremor effect with continued therapy • L Dopa less effective in eliminating postural instability and shuffling gait

11. Effects of L Dopa on Behavior • L Dopa partially changes mood by elevating mood • L Dopa increases patient sense of well being

12. Effects of L Dopa on Cardiovascular System • cardiac stimulation due to beta adrenergic effect on heart • Elderly- transient tachycardia, cardiac arrhythmias and hypertension

13. Effects of L Dopa on Gastrointestinal System • Nausea, Vomiting, and Anorexia • Abdominal Pain • Diarrhea and Constipation • May cause activation of Peptic Ulcer

14. Synthetic Dopamine Agonists • mimic the effect of dopamine by binding directly with the post-synaptic dopamine receptors • Bromocriptine, pergolideand lisuride • tetracyclic ergot derivatives • longerplasma half-lives

15. Synthetic Dopamine Agonists • The nonergot dopamine agonists ropinirole and pramipexole • higher doses, they produce similar side effects

17. Protective Therapy • treat the underlyingpathogenesis of Parkinson's disease so that neurodegenerationis prevented or delayed • Possiblemechanisms of cell damage : • Autoimmunity • excessive excitatorydrive • disturbance of trophic factors • increase inthe concentration of toxic free radicals

18. Protective Therapy • vitamins • co-enzyme Q10 • dopamine agonists • monoamine oxidase type B (MAOB) inhibitors.

19. Management of Different Stages of Disease • Newly Diagnosed Parkinson's Disease • Hoehn-Yahrstage I • thepatient has minor symptoms that are not sufficiently troublesometo affect routine daily activities • selegiline,levodopa, or a synthetic dopamine agonist or no pharmacotherapy

20. National Collaborating Centre for Chronic Conditions. Parkinson’s disease: national clinical guideline for diagnosis and management in primary and secondary care. London: Royal College of Physicians, 2006.

22. Levodopa

23. Dopamine Agonist

24. Monoamine oxidase type B(MAOB) inhibitors

25. ono

26. Beta Adrenergic agents

27. Amantadine

28. Anticholinergics

29. Severe Parkinson's Disease • Management is directed toward decreasing thedose of the drug causing the most troublesome sideeffects and raising the dose of an alternativedrug

31. Levodopa

32. Dopamine agonist

33. MOAB inhibitors

34. COMT

35. Amantadine

36. Management of Adverse Reactions to Therapy • nausea and hypotension • associated with peak plasma concentrationsof dopaminomimetic agent • minimized by taking themedications after light meals or snacks. • Domperidone10 to 20mg

37. Management of Adverse Reactions to Therapy • Hypotension • increased intake of water and salt • fludrocortisone 0.1 mg once or bid • midodrine 2.5 to 20 mg

38. Management of Adverse Reactions to Therapy • Dyskinesia, fluctuations in mobility • unpredictable "on-off" reactions • predictable "wearing-off" effects • Avoid high protein meals

39. Management of Adverse Reactions to Therapy • Psychiatric side effects • confusion, visual hallucinations, and paranoia • beginas nocturnal phenomena • Neurolepticdrugs in general are contraindicated

40. Thank you

41. Structure of the Dopamine D2A Receptor Calne D. N Engl J Med 1993;329:1021-1027

42. Dopamine D1A Receptor Coupled to a G Protein and Linked to AdenylateCyclase in a Striatal Neuron Calne D. N Engl J Med 1993;329:1021-1027

43. Dopamine D1A Receptor Coupled to a G Protein and Linked to AdenylateCyclase in a Striatal Neuron Calne D. N Engl J Med 1993;329:1021-1027

45. Agents that Increase Dopamine functions • Increasing the synthesis of dopamine - l-Dopa • Inhibiting the catabolism of dopamine - selegiline • Stimulating the dopamine receptor sites directly - bromocriptine & pramipexole • Blocking the uptake and enhancing the release of dopamine - amantadine